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Zyvox linezolid Tablets, injection, suspension

2. Overview. Clinical pharmacologyClinical/statistical analyses of efficacyClinical/statistical analyses of safetyDevelopment of resistance. 3. Clinical pharmacology: Pharmacokinetics. 4. Clinical pharmacology: Pharmacokinetics. With 600 mg bid dosing:AUC (PO) = 68 - 209 gh/mLAfter normalization for body weight,AUC = 11.2 - 23.8 gh/mL.

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Zyvox linezolid Tablets, injection, suspension

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    1. 1 Zyvox™ (linezolid) Tablets, injection, suspension NDAs 21-130, 21-131, 21-132 FDA presentation Anti-Infective Drugs Advisory Committee March 24, 2000

    2. 2 Overview Clinical pharmacology Clinical/statistical analyses of efficacy Clinical/statistical analyses of safety Development of resistance

    3. 3 Clinical pharmacology: Pharmacokinetics

    4. 4 Clinical pharmacology: Pharmacokinetics With 600 mg bid dosing: AUC (PO) = 68 - 209 µg·h/mL After normalization for body weight, AUC = 11.2 - 23.8 µg·h/mL

    5. 5 Clinical pharmacology: Metabolism and excretion Metabolism two major metabolites; toxicity not characterized Excretion 35% in urine as parent drug 50% in urine as metabolites 10% in feces as metabolites Metabolites accumulate in patients with renal impairment

    6. 6 Efficacy Analyses

    7. 7 Clinical studies Community-acquired pneumonia Study 33 (CAP in inpatients) Study 51 (CAP in outpatients) Hospital-acquired pneumonia (Study 48A) Skin/skin structure infections Studies 39A/39 (uncomplicated SSSI) Study 55 (complicated SSSI) MRSS infections (Study 31) VRE infections (Studies 54A/54)

    8. 8 Differences in outcome assessment

    9. 9 Analytic populations Randomized patients ITT (all treated patients) MITT (pathogen isolated)

    10. 10 Community-acquired pneumonia

    11. 11 Community-acquired pneumonia (Study 33) Population: 747 inpatients with CAP Design: Multi-center, multi-national, randomized, comparative, open-label Treatment arms (7-14 d treatment duration) Linezolid 600 mg IV q12h /600 mg po q12h Ceftriaxone 1 g IV q12h /Cefpodoxime 200 mg po bid Aztreonam allowed for Gram-negative infections 1ş endpoint: Microbiologic outcome

    12. 12 Study 33 (Inpatient CAP) Demographics

    13. 13 Study 33 (inpatient CAP) Patient populations

    14. 14 Study 33 (inpatient CAP) Clinical efficacy results

    15. Study 33 (inpatient CAP) 95% confidence intervals

    16. 16 Study 33 (inpatient CAP) Results by pathogen (ME patients)

    17. 17 Study 33 (inpatient CAP) Subgroup analyses (CE patients)

    18. 18 Study 33 (inpatient CAP) Effect of missing data

    19. 19 Community-acquired pneumonia (Study 51) Study population: 540 outpatients with CAP Design: Multi-center, multi-national, randomized, comparative, evaluator-blind Treatment arms ( 10-14 d treatment duration) Linezolid 600 mg po q12h Cefpodoxime 200 mg po q12h 1ş endpoint: Clinical outcome

    20. 20 Study 51 (Outpatient CAP) Demographics

    21. 21 Study 51 (outpatient CAP) Patient populations

    22. 22 Study 51 (outpatient CAP) Clinical efficacy results

    23. Study 51 (outpatient CAP) 95% confidence intervals

    24. 24 Study 51 (outpatient CAP) Results by pathogen (ME patients)

    25. 25 Study 51 (outpatient CAP) Subgroup analyses (CE patients)

    26. 26 Study 51 (outpatient CAP) Effect of missing data

    27. 27 Hospital-acquired pneumonia

    28. 28 Hospital-acquired pneumonia (Study 48A) Study population: 396 patients with HAP Design: Multi-center, multi-national, randomized, comparative, double-blind Treatment arms (7-21 d treatment duration) Linezolid 600 mg IV q12h ± Aztreonam 1-2 g IV q8h Vancomycin 1 g IV q12h ± Aztreonam 1-2 g IV q8h 1° endpoints: Clinical/microbiologic outcomes

    29. 29 Study 48A (HAP) Demographics

    30. 30 Study 48A (HAP) Patient populations

    31. 31 Study 48A (HAP) Clinical efficacy results

    32. Study 48A (HAP) 95% confidence intervals

    33. 33 Study 48A (HAP) Results by pathogen (ME patients)

    34. 34 Study 48A (HAP) Subgroup analyses (ME patients)

    35. 35 Study 48A (HAP) Subgroup analyses (MITT patients)

    36. 36 Study 48A (HAP) Effect of missing data

    37. 37 Study 48A (HAP) Mortality rates

    38. 38 Uncomplicated skin and skin structure infections (uSSSI)

    39. 39 Study 39A/39 (uSSSI) Description Population: 753 North American (39A), 332 Non-North American patients (39) Design: Multi-center, randomized, comparative, double-blind Treatment arms (7-14 d treatment duration) Linezolid 400 mg po q12h Clarithromycin 250 mg po q12h 1ş endpoints: Clinical/microbiologic outcomes

    40. 40 Study 39A (uSSSI) Demographics

    41. 41 Study 39A (uSSSI) Patient populations

    42. 42 Study 39A (uSSSI) Clinical efficacy results

    43. Study 39A (uSSSI) 95% confidence intervals

    44. 44 Study 39A (uSSSI) Results by pathogen

    45. 45 Study 39A (uSSSI) Effect of missing data

    46. 46 Study 39 (uSSSI) Demographics

    47. 47 Study 39 (uSSSI) Patient populations

    48. 48 Study 39 (uSSSI) Clinical efficacy results

    49. Study 39 (uSSSI) 95% confidence intervals

    50. 50 Study 39 (uSSSI) Results by pathogen

    51. 51 Complicated skin and skin structure infections (cSSSI)

    52. 52 Complicated skin/skin structure infections (Study 55) Population: 819 patients with cSSSI Study design: Multi-center, multi-national, randomized, comparative, double-blind Treatment arms (10-21 d treatment duration) Linezolid 600 mg IV q12h / Linezolid 600 mg po bid Oxacillin 2 g IV q6h / Dicloxacillin 500 mg po q6h 1° endpoints: Clinical/microbiological outcomes

    53. 53 Study 55 (cSSSI) Demographics

    54. 54 Study 55 (cSSSI) Patient populations

    55. 55 Study 55 (cSSSI) Clinical efficacy results

    56. Study 55 (cSSSI) 95% confidence intervals

    57. 57 Study 55 (cSSSI) Results by pathogen

    58. 58 Study 55 (cSSSI) Subgroup analyses

    59. 59 Study 55 (cSSSI) Effect of missing data

    60. 60 Methicillin-resistant staphylococcal species (MRSS) infections

    61. 61 MRSS infections (Study 31) Population: 460 patients with MRSS infection (Pneumonia, SSSI, UTI, BUO) Design: Multi-center, multi-national, randomized, comparative, open-label Treatment arms (7-28 treatment duration) Linezolid 600 mg IV q12h Vancomycin 1 g IV q12h Concomitant aztreonam/gentamicin allowed 1° endpoints: Clinical/microbiologic outcomes

    62. 62 Study 31 (MRSS) Demographics

    63. 63 Study 31 (MRSS) Patient populations

    64. 64 Study 31 (MRSS) Clinical efficacy results

    65. Study 31 (MRSS) 95% confidence intervals

    66. 66 Study 31 (MRSS) Results by pathogen (ME patients)

    67. 67 Study 31 (MRSS) Results by pathogen (MITT patients)

    68. 68 Study 31 (MRSS) Outcome by site of MRSA infection (ME)

    69. 69 Study 31 (MRSS) Outcome by site of MRSA infection (MITT)

    70. 70 Study 31 (MRSS) Effect of missing data

    71. 71 Vancomycin-resistant enterococcal (VRE) infections

    72. 72 VRE infections (Study 54A) Population: 145 adult patients with known or suspected VRE infection (SST, UTI, BUO, IABD) Design: Multi-center, randomized, dose-comparison, double-blind, superiority Treatment arms Linezolid 600 mg IV q12h Linezolid 200 mg IV q12h Concomitant aztreonam or aminoglycosides allowed 1ş endpoint: Clinical outcome

    73. 73 Study 54A (VRE) Demographics

    74. 74 Study 54A (VRE) Patient populations

    75. 75 Study 54A (VRE) Efficacy results

    76. 76 Study 54A (VRE) Results by pathogen

    77. 77 Study 54A (VRE) Outcome by site of VRE infection

    78. 78 Covariate analyses Covariate analyses were not prespecified Multivariate analysis performed by FDA using: Risk of mortality at baseline 1ş diagnosis Age, sex, weight Bacteremia Adjusted and unadjusted results consistent

    79. 79 Study 54A (VRE) Effect of missing data

    80. 80 Study 54A (VRE) All-cause mortality rates

    81. 81 Causes of death in patients with VRE bacteremia High dose VRE infection (1) Sepsis (2) Respiratory failure (1) Low dose VRE infection (3) Sepsis (1) Pneumonia (1) GVHD (1) AIDS (1) Gastric cancer (1) Liver rejection (1)

    82. 82 Covariate analysis of mortality in bacteremic patients Not prespecified Covariates included: Risk of mortality at baseline Age Sex Adjusted and unadjusted results consistent

    83. 83 History: Studies 54A & 54 Study 54 originally planned for 500 patients In 6/99, blinded decision to submit patients already enrolled as Study 54A (145 patients) Submitted as stand-alone study “all alpha spent” on this trial Study 54 continued as “supportive trial” Data on 82 patients submitted to FDA in 12/99 Bolstering NS results of 54A with these results could correspond to multiple looks without appropriate (prespecified) statistical adjustment

    84. 84 Study 54 (VRE) Efficacy results

    85. 85 Safety analysis Clinical adverse events Laboratory adverse events Potential drug-drug interactions

    86. 86 Adverse events

    87. 87 Adverse events

    88. 88 Drug-related adverse events

    89. 89 Discontinuations due to AEs

    90. 90 Discontinuations due to drug-related AEs

    91. 91 Discontinuations by adverse event

    92. 92 Discontinuations by drug-related AE

    93. 93 Laboratory findings

    94. 94 Comparator-controlled studies: Development of thrombocytopenia*

    95. 95 Comparator-controlled studies: Grade III thrombocytopenia*

    96. 96 Effect of linezolid dose on development of thrombocytopenia*

    97. 97

    98. 98 Summary: thrombocytopenia in linezolid-treated patients Incidence was 1 - 13% (grade III: 0-2.5%), depending on patient population Higher doses associated with ? incidence Thrombocytopenia appeared to resolve in patients with laboratory follow-up No related adverse events identified No apparent effect on other cell lines

    99. 99 Drug-drug interactions

    100. 100 MAO inhibition

    101. 101 Linezolid-sympathomimetic amine interactions

    102. 102 Selected concomitant medications

    103. 103 Potential drug-drug interaction events Database examined for potential MAOI-associated drug-drug interaction events Only small numbers of events found No clear association between adverse events examined and use of concomitant medications Classic MAOI-associated events not seen No hypertensive crises No cases of serotonin syndrome

    104. 104 Linezolid resistance

    105. 105 Linezolid resistance Has been induced in laboratory Mechanism - G ? U on 23S rRNA Frequency < 1 in 109 May result in cross-resistance to lincosamides and chloramphenicol

    106. 106 Linezolid resistance in clinical trials Only seen with Enterococcus spp. Fifteen cases in NDA database as of 12/31/99 9/15 in compassionate use study (Study 25) 6/15 in dose-comparison studies (Studies 54A/54) Mean duration of therapy was 32 ± 9.9 d 14/15 cases were E. faecium; 1/15 was E. faecalis Increase in MIC to: 8 µg/mL (6 isolates) 16 µg/mL (8 isolates) 32 µg/mL (1 isolate - E. faecalis)

    107. 107 Linezolid resistance in compassionate use trial (Study 25) 9/15 occurred during compassionate use 8/9 E. faecium, 1/ 9 E. faecalis 6/9 patients considered failures 3/9 patients considered cured

    108. 108 Linezolid resistance in dose-comparison trials 6/15 occurred in studies 54A/54 (all E. faecium) 4 in low-dose group; 3/4 considered failures 2 in high-dose group; 1/2 considered failures

    109. 109 Linezolid Review Team Biopharmaceutics Jenny Zheng, Ph.D. Frank Pelsor, Ph.D. (TL) Chemistry Jim Timper, M.S. David Katague, Ph.D. (TL) Clinical John Alexander, M.D. David Ross, M.D., Ph.D. Janice Soreth, M.D. (TL) Microbiology Fred Marsik, Ph.D. Albert Sheldon, Ph.D. (TL) Pharm/Tox Ken Seethaler, Ph.D. Robert Osterberg, Ph.D., R.Ph. (TL) Project Management Beth Duvall-Miller, B.S. Statistics Erica Brittain, Ph.D. Joel Jiang, Ph.D. Daphne Lin, Ph.D. (TL) Supervisory Review Gary Chikami, M.D. (DAIDP) Sandra Kweder, M.D. (ODE IV) Dianne Murphy, M.D. (ODE IV)

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